A nonsynonymous single‐nucleotide polymorphism in the PDZ‐Rho guanine nucleotide exchange factor (Ser1416Gly) modulates the risk of lung cancer in Mexican Americans

Gu, Jian; Wu, Xifeng; Dong, Qiong; Romeo, Martin J.; Lin, Xin; Gutkind, J. Silvio; Berman, David M.

doi:10.1002/cncr.21944

Cited by 18 publications

(18 citation statements)

References 43 publications

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“…RGS20 belongs to a family of proteins with conserved GTPase-activating domain of approximately 120 amino acid residues. Previously, polymorphisms of RGS2 and RGS6 genes were described in bladder and lung cancers (53,54). RGS20 itself was reported in stabilizing the microtubule filaments (55).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

Kovářová

Plachý

Kosla

et al. 2013

Molecular Cancer Research

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Comparing the gene expression profiles of metastatic and nonmetastatic cells has the power to reveal candidate metastasis-associated genes, whose involvement in metastasis can be experimentally tested. In this study, differentially expressed genes were explored in the v-src-transformed metastatic cell line PR9692 and its nonmetastatic subclone PR9692-E9. First, the contribution of homeodomain only protein X (HOPX) in metastasis formation and development was assessed. HOPX-specific knockdown decreased HOPX expression in the nonmetastatic subclone and displayed reduced cell motility in vitro. Critically, HOPX knockdown decreased the in vivo metastatic capacity in a syngeneic animal model system. Genomic analyses identified a cadre of genes affected by HOPX knockdown that intersected significantly with genes previously found to be differentially expressed in metastatic versus nonmetastatic cells. Furthermore, 232 genes were found in both screens with at least a two-fold change in gene expression, and a number of high-confidence targets were validated for differential expression. Importantly, significant changes were demonstrated in the protein expression level of three metastaticassociated genes (NCAM, FOXG1, and ITGA4), and knockdown of one of the identified HOPX-regulated metastatic genes, ITGA4, showed marked inhibition of cell motility and metastasis formation. These data demonstrate that HOPX is a metastasis-associated gene and that its knockdown decreases the metastatic activity of v-src-transformed cells through altered gene expression patterns.

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Section: Discussionmentioning

confidence: 99%

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

Kovářová

Plachý

Kosla

et al. 2013

Molecular Cancer Research

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“…An RGS6 enhancer could also be beneficial as a novel cancer therapeutic. RGS6 has been proposed as a tumour suppressor in several types of cancer, including bladder, lung and breast cancer (Berman et al, 2004;Gu et al, 2006;Maity et al, 2011;Maity et al, 2013). While the effects of RGS6 in the CNS seem to mainly be mediated through is canonical GAP activity, its action as a tumour suppressor is mediated through non-G protein mechanisms (Maity et al, 2011).…”

Section: Regulation Of Function Localization and Expressionmentioning

confidence: 99%

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Sjögren

2017

British J Pharmacology

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Regulators of G protein signalling (RGS) proteins are celebrating the 20th anniversary of their discovery. The unveiling of this new family of negative regulators of G protein signalling in the mid-1990s solved a persistent conundrum in the G protein signalling field, in which the rate of deactivation of signalling cascades in vivo could not be replicated in exogenous systems. Since then, there has been tremendous advancement in the knowledge of RGS protein structure, function, regulation and their role as novel drug targets. RGS proteins play an important modulatory role through their GTPase-activating protein (GAP) activity at active, GTP-bound Gα subunits of heterotrimeric G proteins. They also possess many non-canonical functions not related to G protein signalling. Here, an update on the status of RGS proteins as drug targets is provided, highlighting advances that have led to the inclusion of RGS proteins in the IUPHAR/BPS Guide to PHARMACOLOGY database of drug targets.Abbreviations DEP, Disheveled Egl-10 Pleckstrin; GAP, GTPase-activating protein; GGL, G protein γ-like; PPI, protein-protein interaction; RGS, regulator of G protein signalling; R7BP, R7 binding protein; R9AP, RGS9 associated protein IntroductionG protein-mediated signalling pathways have played a pivotal role in drug discovery and development for many decades. The large family of GPCRs or their downstream effectors are the target of 40% of clinically used drugs and thus represent a multi-billion-dollar industry (Wise et al., 2002). Interestingly, of the more than 300 non-olfactory GPCRs known, only a fraction of them are targeted by drugs. Thus, there is a large untapped area of drug development still available. Moreover, many GPCR drugs are associated with low efficacy and/or side effects. More targeted therapies are therefore required, and as we learn more about the structure and function of GPCRs and their regulators, these goals will be achievable.All biological signals are tightly regulated and for every on-switch there is usually an off-switch. GPCRs are activated by ligands, transmitting signalling information to Gα subunits of heterotrimeric G proteins by enhancing the exchange of GDP for GTP in the Gα nucleotide binding site, which results in the dissociation of Gα from Gβγ dimers and activation of both G protein components. Deactivation of G proteins does not occur by simple reversal of nucleotide exchange, but rather by an independently regulated GTPase activity, hydrolyzing GTP to GDP. Although Gα proteins possess an intrinsic ability to hydrolyze GTP, this process is very slow and cannot account for the transient nature of intracellular signalling cascades in vivo. Hence, additional kinetic mechanisms are required for the physiological timing of signals. One of the most critical of these kinetic mechanisms is mediated through regulator of G protein signalling (RGS) proteins, which have received increasing interest as novel drug targets in the past two decades. As a result, RGS proteins have now been added as the most recent ad...

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“…PDZ-RhoGEF, like its homologues LARG and p115-RhoGEF, is specific to RhoA and is activated by the G␣ 12/13 subunit of G-protein coupled receptors via its regulator of G-protein signaling domain. Interestingly, PDZ-RhoGEF single nucleotide polymorphisms have been associated with type II diabetes (3) and lung cancer (4).…”

mentioning

confidence: 99%

Real-time NMR Study of Guanine Nucleotide Exchange and Activation of RhoA by PDZ-RhoGEF

Gasmi-Seabrook

Marshall

Cheung

et al. 2010

Journal of Biological Chemistry

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Small guanosine triphosphatases (GTPases) become activated when GDP is replaced by GTP at the highly conserved nucleotide binding site. This process is intrinsically very slow in most GTPases but is significantly accelerated by guanine nucleotide exchange factors (GEFs). Nucleotide exchange in small GTPases has been widely studied using spectroscopy with fluorescently tagged nucleotides. However, this method suffers from effects of the bulky fluorescent moiety covalently attached to the nucleotide. Here, we have used a newly developed real-time NMRbased assay to monitor small GTPase RhoA nucleotide exchange by probing the RhoA conformation. We compared RhoA nucleotide exchange from GDP to GTP and GTP analogues in the absence and presence of the catalytic DH-PH domain of PDZ-RhoGEF (DH-PH PRG ). Using the non-hydrolyzable analogue guanosine-5-O-(3-thiotriphosphate), which we found to be a reliable mimic of GTP, we obtained an intrinsic nucleotide exchange rate of 5.5 ؋ 10 ؊4 min ؊1 . This reaction is markedly accelerated to 1179 ؋ 10 ؊4 min ؊1 in the presence of DH-PH PRG at a ratio of 1:8,000 relative to RhoA. Mutagenesis studies confirmed the importance of Arg-868 near a conserved region (CR3) of the Dbl homology (DH) domain and revealed that Glu-741 in CR1 is critical for full activity of DH-PH PRG , together suggesting that the catalytic mechanism of PDZ-RhoGEF is similar to Tiam1. Mutation of the single RhoA (E97A) residue that contacts the pleckstrin homology (PH) domain rendered the mutant 10-fold less sensitive to the activity of DH-PH PRG . Interestingly, this mutation does not affect RhoA activation by leukemia-associated RhoGEF (LARG), indicating that the PH domains of these two homologous GEFs may play different roles.The small GTPase 3 RhoA, a member of the Ras superfamily, plays a crucial role in cellular processes including proliferation, movement, cell shape, as well as cell-cell and cell-matrix interactions (1). RhoA acts as a molecular switch, cycling between the inactive GDP-and activated GTP-bound states (Fig. 1A). Akin to other small GTPases, RhoA contains a phosphate binding loop (P-loop) and two switch regions that undergo conformational changes upon nucleotide cycling and mediate interactions with effector proteins. Together these three regions interact with the nucleotide phosphate groups and a magnesium ion that is required for high affinity nucleotide binding (low nM to sub nM K d ). GTPase-activating proteins catalyze nucleotide hydrolysis, thus inactivating GTPases, whereas guanine nucleotide exchange factors (GEFs) activate GTPases by stimulating nucleotide exchange (2). PDZ-RhoGEF, like its homologues LARG and p115-RhoGEF, is specific to RhoA and is activated by the G␣ 12/13 subunit of G-protein coupled receptors via its regulator of G-protein signaling domain. Interestingly, PDZ-RhoGEF single nucleotide polymorphisms have been associated with type II diabetes (3) and lung cancer (4).RhoGEFs are multidomain proteins (5), most of which contain a conserved catalytic Dbl homology (DH) ...

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A nonsynonymous single‐nucleotide polymorphism in the PDZ‐Rho guanine nucleotide exchange factor (Ser1416Gly) modulates the risk of lung cancer in Mexican Americans

Cited by 18 publications

References 43 publications

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Real-time NMR Study of Guanine Nucleotide Exchange and Activation of RhoA by PDZ-RhoGEF

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